Over the last decade, studies have revealed that diminishing mutant huntingtin levels in mouse models of Huntington's disease (HD) leads to the amelioration of pre-existing symptoms, raising the tantalizing possibility for a cure. One of the primary events that accompany symptomatic reversal is the concomitant clearance of the aggregated mutant protein. Despite the intense debate that surrounds the role of protein aggregation in the pathogenesis of HD, a great amount of effort has been put forward to inhibit or disaggregate these proteinaceous intracellular deposits, with limited success. More recently, efforts to drive the turnover of these structures have been proposed, with some promise. One difficulty with these studies has been the inability to target protein degradation pathways in such a way to either enhance or impede the selective elimination of the aggregates, often leading to unwanted, nonspecific consequences that obscure the interpretation of the studies outcome. Recent studies have emerged demonstrating that the protein degradation pathway macroautophagy is capable of the selective degradation of various cargo including ubiquitinated protein aggregates. We have identified the Autophagy linked FYVE domain protein (Alfy) as essential to this process: Importantly not only does depletion of Alfy inhibit the macroautophagic clearance of aggregated mutant htt, but it does so without inhibiting basal and starvation-mediated macroautophagy. Moreover, over-expression of Alfy in neurons led to fewer mutant huntingtin inclusions. In response to the PAS-10-183 Validation of Novel Therapeutic Targets for Huntington's disease, we propose to use Alfy to genetically determine whether the clearance of aggregated mutant huntingtin represents a valid therapeutic approach in HD. PUBLIC HEALTH RELEVANCE: Huntington's disease is a devastating, inherited neurodegenerative disorder that affects 5 to 10 persons per every 100,000. By understanding the cellular events that affect the disease may not only help cure HD, but may also shed insight into sporadic disorders such as Parkinson's disease, Alzheimer's disease and Lou Gehrig's disease. Our goal is to determine if the elimination of protein aggregates, a common feature across most adult onset neurodegenerative diseases, represents a viable therapeutic strategy.